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Arginine 199 and Leucine 208 Have Key Roles in the Control of Adenosine A2A Receptor Signalling Function  [PDF]
Nicolas Bertheleme, Annette Strege, Sorrel E. Bunting, Simon J. Dowell, Bernadette Byrne
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089613
Abstract: One successful approach to obtaining high-resolution crystal structures of G-protein coupled receptors is the introduction of thermostabilising mutations within the receptor. This technique allows the generation of receptor constructs stabilised into different conformations suitable for structural studies. Previously, we functionally characterised a number of mutants of the adenosine A2A receptor, thermostabilised either in an agonist or antagonist conformation, using a yeast cell growth assay and demonstrated that there is a correlation between thermostability and loss of constitutive activity. Here we report the functional characterisation of 30 mutants intermediate between the Rag23 (agonist conformation mutant) and the wild-type receptor using the same yeast signalling assay with the aim of gaining greater insight into the role individual amino acids have in receptor function. The data showed that R199 and L208 have important roles in receptor function; substituting either of these residues for alanine abolishes constitutive activity. In addition, the R199A mutation markedly reduces receptor potency while L208A reduces receptor efficacy. A184L and L272A mutations also reduce constitutive activity and potency although to a lesser extent than the R199A and L208A. In contrast, the F79A mutation increases constitutive activity, potency and efficacy of the receptor. These findings shed new light on the role individual residues have on stability of the receptor and also provide some clues as to the regions of the protein responsible for constitutive activity. Furthermore, the available adenosine A2A receptor structures have allowed us to put our findings into a structural context.
Adenosine A2A receptor binding profile of two antagonists, ST1535 and KW6002: consideration on the presence of atypical adenosine A2A binding sites  [PDF]
Teresa Riccioni,Fabiana Leonardi,Franco Borsini
Frontiers in Psychiatry , 2010, DOI: 10.3389/fpsyt.2010.00022
Abstract: Adenosine A2A receptors seem to exist in typical (more in striatum) and atypical (more in hippocampus and cortex) subtypes. In the present study, we investigated the affinity of two adenosine A2A receptor antagonists, ST1535 [2 butyl -9-methyl-8-(2H-1,2,3-triazol 2-yl)-9H-purin-6-xylamine] and KW6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6,dione] to the “typical” and “atypical” A2A binding sites. Affinity was determined by radioligand competition experiments in membranes from rat striatum and hippocampus. Displacement of the adenosine analog [3H]CGS21680 [2-p-(2-carboxyethyl)phenethyl-amino-5’-N-ethylcarbox-amidoadenosine] was evaluated in the absence or in the presence of either CSC [8-(3-chlorostyryl)-caffeine], an adenosine A2A antagonist that pharmacologically isolates atypical binding sites, or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A1 receptor antagonist that pharmacologically isolates typical binding site. ZM241385 [84-(2-[7-amino-2-(2-furyl) [1,2,4]-triazol[2,3-a][1,3,5]triazin-5-yl amino]ethyl) phenol)] and SCH58261 [(5-amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine], two other adenosine A2A receptor antagonists, which were reported to differently bind to atypical and typical A2A receptors, were used as reference compounds. ST1535, KW6002, ZM241385 and SCH58261 displaced [3H]CGS21680 with higher affinity in striatum than in hippocampus. In hippocampus, no typical adenosine A2A binding was detected, and ST1535 was the only compound that occupied atypical A2A adenosine receptors. Present data are explained in terms of heteromeric association among adenosine A2A, A2B and A1 receptors, rather than with the presence of atypical A2A receptor subtype.
Gestational Diabetes Reduces Adenosine Transport in Human Placental Microvascular Endothelium, an Effect Reversed by Insulin  [PDF]
Carlos Salomón, Francisco Westermeier, Carlos Puebla, Pablo Arroyo, Enrique Guzmán-Gutiérrez, Fabián Pardo, Andrea Leiva, Paola Casanello, Luis Sobrevia
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040578
Abstract: Gestational diabetes mellitus (GDM) courses with increased fetal plasma adenosine concentration and reduced adenosine transport in placental macrovascular endothelium. Since insulin modulates human equilibrative nucleoside transporters (hENTs) expression/activity, we hypothesize that GDM will alter hENT2-mediated transport in human placental microvascular endothelium (hPMEC), and that insulin will restore GDM to a normal phenotype involving insulin receptors A (IR-A) and B (IR-B). GDM effect on hENTs expression and transport activity, and IR-A/IR-B expression and associated cell signalling cascades (p42/44 mitogen-activated protein kinases (p42/44mapk) and Akt) role in hPMEC primary cultures was assayed. GDM associates with elevated umbilical whole and vein, but not arteries blood adenosine, and reduced hENTs adenosine transport and expression. IR-A/IR-B mRNA expression and p42/44mapk/Akt ratios (‘metabolic phenotype’) were lower in GDM. Insulin reversed GDM-reduced hENT2 expression/activity, IR-A/IR-B mRNA expression and p42/44mapk/Akt ratios to normal pregnancies (‘mitogenic phenotype’). It is suggested that insulin effects required IR-A and IR-B expression leading to differential modulation of signalling pathways restoring GDM-metabolic to a normal-mitogenic like phenotype. Insulin could be acting as protecting factor for placental microvascular endothelial dysfunction in GDM.
A2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE–knockout mice
Teng B, Mustafa SJ
Journal of Experimental Pharmacology , 2011, DOI: http://dx.doi.org/10.2147/JEP.S18945
Abstract: 2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE–knockout mice Original Research (1960) Total Article Views Authors: Teng B, Mustafa SJ Published Date July 2011 Volume 2011:3 Pages 59 - 68 DOI: http://dx.doi.org/10.2147/JEP.S18945 Bunyen Teng, S Jamal Mustafa Department of Physiology and Pharmacology and Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USA Abstract: Adenosine-induced coronary vasodilation is predominantly A2A adenosine receptor (AR)-mediated, whereas A1 AR is known to negatively modulate the coronary flow (CF). However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not well understood. Using hyperlipidemic/atherosclerotic apolipoprotein E (APOE)–knockout mice, CF responses to nonspecific adenosine agonist (5'-N-ethylcarboxamide adenosine, NECA) and specific adenosine agonists (2-chloro-N6-cyclopentyl-adenosine [CCPA, A1 AR-specific] and CGS-21680, A2A AR-specific) were assessed using isolated Langendorff hearts. Western blot analysis was performed in the aorta from APOE and their wild-type (WT) control (C57BL/6J). Baseline CF (expressed as mL/min/g heart weight) was not different among WT (13.23 ± 3.58), APOE (13.22 ± 2.78), and APOE on high-fat diet (HFD) for 12 weeks (APOE-HFD, 12.37 ± 4.76). Concentration response curves induced by CGS-21680 were significantly shifted to the left in APOE and APOE-HFD when compared with WT. CCPA induced an increase in CF only at 10-6 M in all groups and the effect was reversed by the addition of a selective A2A AR antagonist, SCH-58261 (10-6 M), and a significant decrease in CF from baseline was observed. Western blot analysis showed a significant upregulation of A2A AR in the aorta from APOE and APOE-HFD. This study provides the first evidence that CF responses to A2A AR stimulation were upregulated in hyperlipidemic/atherosclerotic animals. The speculation is that the use of A2A AR-specific agonist for myocardial perfusion imaging (such as regadenoson) could overestimate the coronary reserve in coronary artery disease patients.
Adenosine A2A Receptors and A2A Receptor Heteromers as Key Players in Striatal Function  [PDF]
Sergi Ferré,César Quiroz,Gemma Navarro,Antonio Cortés,Vicent Casadó,Enric I. Canela,Carme Lluis
Frontiers in Neuroanatomy , 2011, DOI: 10.3389/fnana.2011.00036
Abstract: A very significant density of adenosine A2A receptors (A2ARs) is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs). In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs). In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl cyclase (AC). Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striatopallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs) and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders.
Adenosine A2a receptor agonists as regulators of inflammation: pharmacology and therapeutic opportunities  [cached]
Silvana Morello,Rosalinda Sorrentino,Aldo Pinto
Journal of Receptor, Ligand and Channel Research , 2009,
Abstract: Silvana Morello, Rosalinda Sorrentino, Aldo PintoDepartment of Pharmaceutical Sciences, Biomedical Section, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, Salerno, ItalyAbstract: A2a receptor (A2aR) plays an important role in the regulation of inflammatory and immune responses. The activation of PKA-dependent and/or -independent pathways are responsible for the downmodulation of inflammatory networks and tissue injury. Based on promising recent studies, selective A2aR agonists are under clinical investigations for a wide range of disorders, such as ischemia-reperfusion injury, chronic inflammation, and infectious diseases. Nevertheless, further studies are required to improve our understanding in the ability of A2a receptor agonists to reduce tissue damage during inflammation. Characterization of A2aR-induced signaling pathways will be useful for the development of novel therapeutic strategies in inflammatory/immune diseases.Keywords: adenosine, A2a receptor, A2a receptor agonists, inflammation
NCS-1 associates with adenosine A2A receptors and modulates receptor function  [PDF]
Gemma Navarro,Carmen Lluís,Vicent Casadó,Peter J. McCormick,Michael R. Kreutz,Marina Mikhaylova
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00053
Abstract: Modulation of G protein-coupled receptor (GPCR) signaling by local changes in intracellular calcium concentration is an established function of Calmodulin (CaM) which is known to interact with many GPCRs. Less is known about the functional role of the closely related neuronal EF-hand Ca2+-sensor proteins that frequently associate with CaM targets with different functional outcome. In the present study we aimed to investigate if a target of CaM—the A2A adenosine receptor is able to associate with two other neuronal calcium binding proteins (nCaBPs), namely NCS-1 and caldendrin. Using bioluminescence resonance energy transfer (BRET) and co-immunoprecipitation experiments we show the existence of A2A—NCS-1 complexes in living cells whereas caldendrin did not associate with A2A receptors under the conditions tested. Interestingly, NCS-1 binding modulated downstream A2A receptor intracellular signaling in a Ca2+-dependent manner. Taken together this study provides further evidence that neuronal Ca2+-sensor proteins play an important role in modulation of GPCR signaling.
ADENOSINE A2A RECEPTOR MEDIATES RESERPINE-INDUCED DEPRESSION IN RATS
腺苷A2a受体介导利血平引起的行为性抑郁

Thomas R MINOR,
黄庆军
,郝新玲,Thomas R MINOR

心理学报 , 2003,
Abstract: Intraperitoneal injection of reserpine (4, 6 or 8 mg/kg) increased floating time in the Porsolt swim test in a dose and time dependent manner in rats. Although such behavioral depression usually is attributed to drug induced depletion of brain monoamines, the outcome might be more directly related to brain adenosine signaling associated neuronal overactivation or brain cytokine induction following excitotoxic tissue damage. We addressed these possibilities by pretreating rats with caffeine (7 mg/kg), a high affinity adenosine receptor antagonist, prior to reserpine treatment (6 mg/kg). Caffeine partially reversed the ensuing behavioral depression as measured in the Prosolt swim test conducted 1, 24 and 72 hours after reserpine treatment. Further investigation has also been done to determine the subtype of adenosine receptor, which should mediate reserpine's effect. The results showed that adenosine A2 receptor antagonist (DMPX) and A2a antagonist (CSC) reversed the reserpine induced behavioral depression dose dependently. These results suggest that adenosine mediates reserpine induced depression via adenosine A2a receptor and provide evidence that adenosine plays a crucial role in mediating behavioral depression, which will benefit in understanding the mechanism of depression and finding new drug for anti depressant treatment.
Regulatory effects of adenosine A2A receptors on psychomotor ability and mood behavior of mice  [cached]
Li JIANG,Hong RAN,Wei DUAN,Jian ZHENG
Medical Journal of Chinese People's Liberation Army , 2011,
Abstract: Objective To explore the effects of gene knock-out,agonist or inhibitor of adenosine A2A receptor on the locomotor activity,and anxiety-or depression-like behavior of mice.Methods Male C57BL/6 mice,comprising those underwent gene knock-out of adenosine A2A receptor(A2AKO) and their wild-type(WT) littermates,were assigned into A2AKO group and WT group.Another batch of male C57BL/6,specific-pathogen-free(SPF) mice,were assigned into SCH58261 group,CGS21680 group and control group.Mice of aforesaid 3 groups were transperitoneally administered with SCH58261,a specific inhibitor of adenosine A2A receptor at a dose of 2mg/kg,CGS21680,a specific agonist of adenosine A2A receptor at a dose of 0.5mg/kg,and vehicle(0.25ml,comprising DMSO and saline),respectively.Ten minutes after injection,mice of the 3 groups underwent open-field test,elevated plus-maze test and forced swimming test to detect their locomotor activity,anxiety-and depression-like behavior.Results a) Compared with WT group,the total movement distance decreased(P < 0.001) and the stay time in the peripheral area increased(P < 0.05) in the open-field test,the frequency of entering the open arms and the stay time on the open arms also decreased(P < 0.05) in elevated plus-maze test in the A2AKO group,whereas no significant difference was found between the 2 groups in total immobility time in the forced swimming test(P > 0.05).b) Compared with control group,the total movement distance decreased and the stay time in the peripheral area increased significantly in the open field test(P < 0.01),the frequency of entering the open arms and the stay time on the open arms also decreased(P < 0.01) in elevated plus-maze test,and the total immobility time in forced swimming test increased(P < 0.001) in the CGS21680 group.c) Compared with control group,both the total movement distance and the stay time in the peripheral area increased(P < 0.001),the total immobility time in forced swimming test decreased(P < 0.01) in SCH58261 group,while no significant difference was found in elevated plus-maze test between the two groups(P > 0.05).Conclusions The agonist of adenosine A2A receptor may depress the spontaneous motility and exploratory behavior,and exacerbate the anxiety and depression,and it simulates the effect induced by knock-out of A2A receptor gene,but it is opposite to the effect induced by A2A receptor inhibitor.
A2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE–knockout mice  [cached]
Teng B,Mustafa SJ
Journal of Experimental Pharmacology , 2011,
Abstract: Bunyen Teng, S Jamal MustafaDepartment of Physiology and Pharmacology and Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USAAbstract: Adenosine-induced coronary vasodilation is predominantly A2A adenosine receptor (AR)-mediated, whereas A1 AR is known to negatively modulate the coronary flow (CF). However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not well understood. Using hyperlipidemic/atherosclerotic apolipoprotein E (APOE)–knockout mice, CF responses to nonspecific adenosine agonist (5'-N-ethylcarboxamide adenosine, NECA) and specific adenosine agonists (2-chloro-N6-cyclopentyl-adenosine [CCPA, A1 AR-specific] and CGS-21680, A2A AR-specific) were assessed using isolated Langendorff hearts. Western blot analysis was performed in the aorta from APOE and their wild-type (WT) control (C57BL/6J). Baseline CF (expressed as mL/min/g heart weight) was not different among WT (13.23 ± 3.58), APOE (13.22 ± 2.78), and APOE on high-fat diet (HFD) for 12 weeks (APOE-HFD, 12.37 ± 4.76). Concentration response curves induced by CGS-21680 were significantly shifted to the left in APOE and APOE-HFD when compared with WT. CCPA induced an increase in CF only at 10-6 M in all groups and the effect was reversed by the addition of a selective A2A AR antagonist, SCH-58261 (10-6 M), and a significant decrease in CF from baseline was observed. Western blot analysis showed a significant upregulation of A2A AR in the aorta from APOE and APOE-HFD. This study provides the first evidence that CF responses to A2A AR stimulation were upregulated in hyperlipidemic/atherosclerotic animals. The speculation is that the use of A2A AR-specific agonist for myocardial perfusion imaging (such as regadenoson) could overestimate the coronary reserve in coronary artery disease patients.Keywords: hyperlipidemia, atherosclerosis, apolipoprotein E–knockout mice, coronary flow regulation, A2A adenosine receptor
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